BACKGROUND: The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ-Lin28a axis in restenosis. METHODS: Restenosis and atherosclerosis rat models of type 2 diabetes ( n   =  20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student's t -test and one-way analysis of variance were used for statistical analysis. RESULTS: C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitroC/EBPβ overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBPβ knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBPβ hypomethylation. Additionally, Lin28a overexpression reduced C/EBPβ methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells. CONCLUSION Our findings suggest that the C/EBPβ-Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.
Animals ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Muscle, Smooth, Vascular/metabolism* ; Rats ; DNA Methylation/physiology* ; CCAAT-Enhancer-Binding Protein-beta/genetics* ; Male ; Myocytes, Smooth Muscle/cytology* ; Rats, Sprague-Dawley ; RNA-Binding Proteins/genetics* ; Cells, Cultured ; Coronary Restenosis/metabolism*

OBJECTIVE: To analyze the molecular genetic spectrum of children with acute myeloid leukemia (AML), and explore its correlation with clinical characteristics and prognosis. METHODS: The clinical and molecular genetic data of 116 children with newly diagnosed AML in Wuhan Children's Hospital from September 2015 to August 2022 were retrospectively analyzed. The Fisher's exact test was used to analyze the correlation of gene mutations with clinical features, and Kaplan-Meier curve was used to analyze the influences of gene mutations on the prognosis. RESULTS: NRAS (22%), KRAS (14.9%), and KIT (14.7%) mutations were the most common genetic abnormalities in 116 children with AML. Children with KIT, CEBPA and GATA2 mutations showed a higher median onset-age than those without mutations (all P < 0.05). Children with FLT3-ITD mutation exhibited a higher white blood cell count at initial diagnosis compared to those without mutations (P < 0.05). Children with ASXL2 mutation had lower platelet count and hemoglobin at initial diagnosis than those without mutations (both P < 0.05). KIT mutations were often co-occurred with t(8;21)(q22;q22). There was no significant relationship between gene mutation and minimal residual disease (MRD) remission rate after the first and second induction therapy (P >0.05). KIT and NRAS mutations were not associated with prognosis significantly (P >0.05). The overall survival (OS) rates of children with CEBPA and FLT3-ITD mutations were superior to those without mutations, but the differences were not statistically significant (P >0.05). The 3-year OS rate of 61 children treated by allogeneic hematopoietic stem cell transplantation was 89.8%, which was significantly higher than 55.2% of those only treated by chemotherapy (P < 0.001). CONCLUSIONS Gene mutations are common in children with AML, and next-generation sequencing can significantly improve the detection rate of gene mutations, which can guide the risk stratification therapy. In addition, FLT3-ITD and KIT mutations may no longer be poor prognostic factors.
Humans ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Prognosis ; Retrospective Studies ; fms-Like Tyrosine Kinase 3/genetics* ; Child ; Proto-Oncogene Proteins c-kit/genetics* ; Male ; Female ; CCAAT-Enhancer-Binding Proteins/genetics* ; Membrane Proteins/genetics* ; Child, Preschool ; Adolescent ; GATA2 Transcription Factor/genetics* ; GTP Phosphohydrolases/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics*

Magnolol, a compound extracted from Magnolia officinalis, demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases. Its biological activities encompass anti-inflammatory, antioxidant, anticoagulant, and anti-diabetic effects. Growth/differentiation factor-15 (GDF-15), a member of the transforming growth factor β superfamily, is considered a potential therapeutic target for metabolic disorders. This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism. The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo, and determined the involvement of endoplasmic reticulum (ER) stress signaling in this process. Luciferase reporter assays, chromatin immunoprecipitation, and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4 (ATF4), CCAAT enhancer binding protein γ (CEBPG), and CCCTC-binding factor (CTCF). The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene, as well as the influence of single nucleotide polymorphisms (SNPs) on magnolol and ATF4-induced transcription activity. Results demonstrated that magnolol triggers GDF-15 production in endothelial cells (ECs), hepatoma cell line G2 (HepG2) and hepatoma cell line 3B (Hep3B) cell lines, and primary mouse hepatocytes. The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene. SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15. In high-fat diet ApoE^-/- mice, administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15. These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity, indicating its potential as a drug for the treatment of metabolic disorders.
Lignans/pharmacology* ; Growth Differentiation Factor 15/metabolism* ; Animals ; Biphenyl Compounds/pharmacology* ; Endoplasmic Reticulum Stress/drug effects* ; Activating Transcription Factor 4/genetics* ; Mice ; Humans ; Male ; Magnolia/chemistry* ; CCAAT-Enhancer-Binding Proteins/genetics* ; Mice, Inbred C57BL

OBJECTIVES: We performed an updated meta-analysis to clarify the relationship between the CEBPE rs2239633 polymorphism and the childhood acute lymphoblastic leukemia (CALL) susceptibility. METHODS: All the case-control studies were updated on October 5, 2020, through Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) electronic database. The heterogeneity in the study was tested by the Q test and I RESULTS: A total of 20 case-control studies were selected, including 7014 patients and 16,428 controls. There was no association of CEBPE rs2239633 polymorphism with CALL (CC vs CT + TT: OR = 1.08, 95% CI = 0.94-1.26; CC + CT vs TT: OR = 1.10, 95% CI = 0.94-1.30; C vs T: OR = 1.02, 95% CI = 0.92-1.13). In the subgroup analysis by ethnicity, there is no significant association of this polymorphism and CALL risks among Asian and Caucasian populations in the three genetic models (CC vs CT + TT, CC + CT vs TT, and C vs T). CONCLUSION This meta-analysis found no significant association between the CEBPE rs2239633 polymorphism and susceptibility to CALL.
Adolescent ; CCAAT-Enhancer-Binding Proteins/metabolism* ; Child ; Child, Preschool ; Genetic Predisposition to Disease/genetics* ; Humans ; Infant ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics*

Objective: To analyze the prognostic value of CD7 expression in newly diagnosed acute myeloid leukemia (AML) patients, and to further explore the correlation between CD7 expression and CEBPA mutation, and to clarify the prognostic value of CD7(+) in AML patients with wild-type (WT) or mutant-type (MT) CEBPA. Methods: The clinical data of 298 newly diagnosed non-M(3) AML patients between January 2010 and December 2016 were analyzed retrospectively. The clinical characteristics and prognosis of CD7(+) and CD7(-) patients were respectively compared in all patients, and in patients with WT and MT CEBPA. The relationship between CD7 expression and CEBPA mutation was determined by chi-square, and the effects of CEBPA mutation on survival and prognosis in CD7(+) group by Kaplan-Meier method. Results: In CD7(+) group, the frequencies of CEBPA mutation were 10.1% (single site) and 33.9% (double site) , significantly higher than those of the CD7(-) group (5.3% and 4.2%) (P=0.000) . Subgroup prognostic analysis showed a lower CR rate (P=0.001) and a higher RR (P=0.023) in CD7(+) group comparing to those of CD7(-) group in AML patients with wild type CEBPA. There were no statistical difference between CD7(+) group and CD7(-) group in overall survival (OS) and disease free survival (P>0.05) , while in the CEBPA mutant group the CD7(+) group has higher OS (P=0.019) and DFS (P=0.010) . Based on the CD7 expression and CEBPA mutation, 298 cases were divided into 3 subgroups, named as CD7(+)-CEBPA MT group, CD7(-) and CD7(+)-CEBPA WT group. The 3-year OS of the 3 groups were 80.2%, 48.0% and 30.6%, respectively (P<0.001) , and the 3-year DFS were 74.1%, 37.4% and 22.2%, respectively (P<0.001) . Conclusion: The CEBPA mutation rate was higher in CD7(+) AML patients then that of CD7(-) patients. CD7 expression has opposite prognostic significance in AML patients carrying the wild-type or mutant-type CEBPA. Based on CD7 expression and CEBPA mutation, a new risk stratification model can be established, which is helpful to guide the clinical individualized treatment for AML patients.
CCAAT-Enhancer-Binding Proteins/genetics* ; Disease-Free Survival ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Prognosis ; Retrospective Studies

Adult ; CCAAT-Enhancer-Binding Proteins/genetics* ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Neoplasm, Residual/diagnosis* ; Nuclear Proteins/genetics* ; Nucleophosmin ; Prognosis ; Remission Induction ; fms-Like Tyrosine Kinase 3/genetics*

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing.We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.
Adolescent ; Adult ; Aged ; CCAAT-Enhancer-Binding Proteins ; genetics ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Female ; GTP Phosphohydrolases ; genetics ; Gene Expression Profiling ; Gene Frequency ; Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Leukemia, Myeloid, Acute ; genetics ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Mutation ; Nuclear Proteins ; genetics ; Phenotype ; Retrospective Studies ; Young Adult ; fms-Like Tyrosine Kinase 3 ; genetics

BACKGROUND: To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. METHODS: Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. RESULTS: The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (< or =5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number of t(8;21) patients were analyzed, WT1 mutation status did not affect prognosis significantly. Relapse or death during follow-up occurred more frequently in t(8;21) patients carrying c-KIT mutations than in those without the mutation, although the difference was significant only in a specific patient subgroup with no WT1 mutations (P=0.014). CONCLUSIONS: The incidences of mutations in epigenetic genes are very low in CBF AML; however, c-KIT and WT1 mutations occur more frequently than others. The poor prognostic impact of c-KIT mutation in t(8;21) AML patients only applies in a specific patient subgroup without WT1 mutations. The prognostic impact of WT1 mutation in CBF AML is not evident and further investigation is required.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group/*genetics ; CCAAT-Enhancer-Binding Proteins/*genetics ; Child ; Core Binding Factors/genetics ; Disease-Free Survival ; Epigenesis, Genetic ; Female ; Humans ; Incidence ; Leukemia, Myeloid, Acute/*diagnosis/epidemiology/genetics ; Male ; Middle Aged ; Mutation ; Prognosis ; Proto-Oncogene Proteins c-cbl/*genetics ; Proto-Oncogene Proteins c-kit/*genetics ; Republic of Korea/epidemiology ; Survival Rate ; Translocation, Genetic ; WT1 Proteins/*genetics ; Young Adult

OBJECTIVE: The expression of C/EBPα, CK10 in nasal inverted papilloma (NIP) were detected in the study. Further discussed their significance in genesia, development and recurrence of NIP. METHOD: Three groups including nasal cavity mucosae (NM 10 cases), nasal polyp (NP 20 cases) and NIP (30 cases) were selected in the study. Expretion of C/EBPα, CK10 were detected by immunohistochemisty PV-6000 method. RESULT: (1) The different expression of C/EBPα and CK10 in the group of NM, NP and NIP was statistically significant (P < 0.05). (2) The different expression of C/EBPα, CK10 in the group of benign NIP and NIP with atypical hyperplasia was statistically significant (P < 0.05). (3) The different expression of C/EBPα and CK10 in the group of NIP with recurrence and NIP with no recurrence was statistically significant, P < 0.05, respectively. (4) Our result indicate that the relationship of C/EBPα and CK10 (r = 0.578, P < 0.01) was direct correlation. The difference was statistically significant. CONCLUSION In conclusion, the present results describe C/EBPα, CK10 expression in NIP and their possible implication in the regulation of tumor growth and differentiation. C/EBPα and CK10 production may prove useful in terms of a prognostic marker for the recurrence in nasal inverted papilloma.
CCAAT-Enhancer-Binding Proteins ; genetics ; metabolism ; Humans ; Keratin-10 ; genetics ; metabolism ; Nasal Polyps ; genetics ; metabolism ; Neoplasm Recurrence, Local ; Nose ; Nose Neoplasms ; genetics ; metabolism ; Papilloma, Inverted ; genetics ; metabolism

This study was aimed to explore the clinical characteristics and therapeutic efficacy of normal karyotype AML patients with CEBPA mutations. Fifty-five de novo AML patients with normal karyotype were retrospectively analyzed with regard to frequency of CEBPA mutation, clinical characteristics and therapeutic response. The results showed that CEBPA mutation was detected in 20 patients (36.4%), among them 17 cases displayed double mutations, three cases were with single mutation. The clinical characteristics of patients with CEBPA mutation displayed as follows: 75% of AML patients with CEBPA mutation were AML-M1 and AML-M2, the hemoglobin level at newly diagnosis was higher and the platelet count at newly diagnosis time was lower than those of AML patients without CEBPA mutation [(98.30 ± 20.33) g/L vs (81.69 ± 23.74) g/L (P < 0.05); and (33.30 ± 38.27) ×10(9)/L vs (64.79 ± 61.60) ×10(9)/L (P < 0.05)]. The leukemic cells highly expressed CD7 and CD34. The therapeutic efficacy of 1 cycle for AML patients with CEBPA mutation was satisfactory (72.2%), was higher than that of patients without CEBPA mutation(68.6%), but there was no statistical significance (P > 0.05). It is concluded that AML with CEBPA mutation is more observed in AML-M1 and AML-M2, and accompanies by high level of hemoglobin and lower platelet count, expression of CD7 and CD34. Early-term therapeutic efficacy is satisfactory. The frequency of CEBPA mutation may be higher in Chinese patients with AML compared with that reported in Western world.
Adolescent ; Adult ; CCAAT-Enhancer-Binding Proteins ; genetics ; Child ; Female ; Humans ; Karyotype ; Karyotyping ; Leukemia, Myeloid, Acute ; diagnosis ; genetics ; therapy ; Male ; Middle Aged ; Mutation ; Prognosis ; Retrospective Studies ; Treatment Outcome ; Young Adult